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C5aR2 (C5L2/gp77) is a seven-transmembrane spanning receptor that binds to C5a but lacks motifs essential for G protein coupling and associated signal transduction. C5aR2 is expressed on immune cells, modulates various inflammatory diseases in mice, and has been shown to facilitate murine and human regulatory T cell (T REG ) generation in vitro. Whether and how C5aR2 impacts in vivo T REG generation and pathogenic T cell-dependent disease models have not been established. In this article, we show that murine T cells express and upregulate C5aR2 during induced T REG (iT REG ) generation and that the absence of T cell-expressed C5aR2 limits in vivo iT REG generation following adoptive transfer of naive CD4 + T cells into Rag1  -/- recipients. Using newly generated C5aR2-transgenic mice, we show that overexpression of C5aR2 in naive CD4 + T cells augments in vivo iT REG generation. In a model of T REG -dependent cardiac allograft survival, recipient C5aR2 deficiency accelerates graft rejection associated with lower T REG /effector T cell ratios, whereas overexpression of C5aR2 in immune cells prolongs graft survival associated with an increase in T REG /effector T cell ratios. T cell-expressed C5aR2 modulates T REG induction without altering effector T cell proliferation or cytokine production. Distinct from reported findings in neutrophils and macrophages, T REG -expressed C5aR2 does not interact with β-arrestin or inhibit ERK1/2 signaling. Rather, cumulative evidence supports the conclusion that C5aR2 limits C5aR1-initiated signals known to inhibit T REG induction. Together, the data expand the role of C5aR2 in adaptive immunity by providing in vivo evidence that T cell-expressed C5aR2 physiologically modulates iT REG generation and iT REG -dependent allograft survival.

T Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell (TREG) Generation and TREG-Dependent Cardiac Allograft Survival